The present invention relates to derivatives of formula: 
their salts, their preparation and the medicaments containing them.
In formula (I),
R represents a radical CR1R2, Cxe2x95x90C(R5)SO2R6 or Cxe2x95x90C(R7)SO2alk,
or R1 represents a hydrogen atom and R2 represents a radical xe2x80x94C(R8) (R9) (R10), xe2x80x94C(R8) (R11) (R12), xe2x80x94COxe2x80x94NR13R14, xe2x80x94CH2xe2x80x94COxe2x80x94NR13R14, xe2x80x94CH2xe2x80x94COxe2x80x94R6, xe2x80x94COxe2x80x94R6, xe2x80x94CO-cycloalkyl, xe2x80x94SOxe2x80x94R6, xe2x80x94SO2xe2x80x94R6, xe2x80x94C(OH) (R12) (R6), xe2x80x94C(OH) (R6) (alkyl), xe2x80x94C(xe2x95x90NOalk)R6, xe2x80x94C(xe2x95x90NOxe2x80x94CH2xe2x80x94CHxe2x95x90CH2)R6, xe2x80x94CH2xe2x80x94CH(R6)NR31R32, xe2x80x94CH2xe2x80x94C(xe2x95x90NOalk)R6, xe2x80x94CH(R6)NR31R32, xe2x80x94CH(R6)NHSO2alk, xe2x80x94CH(RP6)NHCONHalk or xe2x80x94CH(R6)NHCOalk,
or R1 represents an alkyl, NHxe2x80x94R15, cyano, xe2x80x94Sxe2x80x94alkxe2x80x94NR16R17, xe2x80x94CH2xe2x80x94NR18R19, or xe2x80x94NR20R21 radical and R2 represents a radical xe2x80x94C(R8) (R11) (R12),
R3 and R4, which are identical or different, represent either an alkyl or cycloalkyl radical, or an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, xe2x80x94COxe2x80x94alk, cyano, xe2x80x94COOH, xe2x80x94COOalk, xe2x80x94CONR22R23, xe2x80x94COxe2x80x94NHxe2x80x94NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alkxe2x80x94NR24R25 radicals; or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94COOH, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHxe2x80x94NR24R25, xe2x80x94CONR22R23, -alkxe2x80x94NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radicals,
R5 represents a hydrogen atom or an alkyl radical,
R6 represents a radical Ar or Het,
R7 represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted by a xe2x80x94CSO-phenyl radical,
R8 represents a hydrogen atom or an alkyl radical,
R9 represents a radical xe2x80x94COxe2x80x94NR26R27, xe2x80x94COOH, xe2x80x94COOalk, xe2x80x94CH2QH, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94alk, xe2x80x94CH2xe2x80x94NHR28 or xe2x80x94NHCOOalk,
R10 represents a radical Ar or Het,
R11 represents a radical xe2x80x94SO2xe2x80x94alk, xe2x80x94SO2xe2x80x94Ar or xe2x80x94SO2xe2x80x94Het,
R12 represents a hydrogen atom or a radical Ar or Het,
R13 represents a hydrogen atom or an alkyl radical,
R14 represents a radical Ar, Het, -alkxe2x80x94Ar or -alk-Het,
R15 represents an alkyl, cycloalkyl or -alkxe2x80x94NR29R30 radical,
R16 and R17, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R16 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals,
R18 represents a hydrogen atom or an alkyl radical,
R19 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, xe2x80x94SO2alk, xe2x80x94COxe2x80x94NHalk or xe2x80x94COOalk radical,
or alternatively R18 and R19 form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals,
xe2x80x94NR20R2, represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen and sulfur,
R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R24 and R25, which are identical or different, represent a hydrogen atom or an alkyl, xe2x80x94COOalk, cycloalkyl, alkylcycloalkyl, -alkxe2x80x94Oxe2x80x94alk or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, xe2x80x94COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk, oxo, hydroxyalkyl, -alkxe2x80x94Oxe2x80x94alk or xe2x80x94COxe2x80x94NH2 radicals,
R26 and R27, which are identical or different, represent a hydrogen atom or an alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alkxe2x80x94COOalk, -alkxe2x80x94Ar, -alk-Het, Het or -alkxe2x80x94N(alk)2 radical, R26 and R27 may also form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy radicals or halogen atoms,
R28 represents a xe2x80x94CH2xe2x80x94alk, benzyl, xe2x80x94SO2alk, xe2x80x94CONHalk, xe2x80x94COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or xe2x80x94COxe2x80x94(CH2)nOH radical,
n is equal to 1, 2 or 3,
R29 and R30, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R29 and R30 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R31 and R32, which are identical or different, represent a hydrogen atom or an alkyl, Ar or -alk-Ar radical or alternatively R31 and R32 together form with the nitrogen atom to which they are attached a heterocycle chosen from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl,
alk represents an alkyl or alkylene radical,
Ar represents a phenyl or naphthyl radical optionally substituted with one or more substituents chosen from a halogen atom or an alkyl, alkoxy, xe2x80x94COxe2x80x94alk, cyano, xe2x80x94COOH, xe2x80x94COOalk, xe2x80x94CONR22R23, xe2x80x94COxe2x80x94NHxe2x80x94NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alkxe2x80x94NR24R25, xe2x80x94NR24R25, alkylthioalkyl, formyl, hydroxyl, CF3, OCF3, Het, xe2x80x94Oxe2x80x94alkxe2x80x94NHxe2x80x94cycloalkyl or SO2NH2 radical,
Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, xe2x80x94CONR22R23, hydroxyl, hydroxyalkyl, oxo or SO2NH2 radicals.
In the preceding definitions and in those which follow, unless otherwise stated, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, the cycloalkyl radicals contain 3 to 10 carbon atoms and the heterocycloalkyl and heterocyclenyl radicals contain 3 to 10 carbon atoms.
Among the alkyl radicals, there may be mentioned the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned the methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
Among the cycloalkyl radicals, there may be mentioned the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.
The heterocycloalkyl radicals are cycloalkyl radicals in which at least one of the carbon atoms is replaced with a heteroatom chosen from nitrogen, sulfur and oxygen. Among these, there may be mentioned the pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl rings.
The heterocyclenyl radicals are cycloalkyl radicals in which at least one carbon atom is replaced with a heteroatom chosen from oxygen, sulfur and nitrogen and which contain at least one carbon-carbon or carbon-nitrogen double bond. Among the heterocyclenyl radicals, there may be mentioned the 1,2,3,4-tetrahydrohydropyridinyl, 3,6-dihydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H-pyrane, dihydrofuranyl and fluorodihydrofuranyl rings. Those preferred are the 3,6-dihydropyridyl rings.
The term halogen comprises chlorine, fluorine, bromine and iodine.
Among the heterocycles representing Het, the following heterocycles may be mentioned: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolyl, piperidyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl and thienyl.
When R3 and/or R4 represent independently a substituted phenyl, the latter is preferably mono-, di- or trisubstituted.
When R16 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R18 and R19 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
The heterocycle formed by NR20R21 is preferably azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl or imidazolyl.
When R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R26 and R27 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R29 and R30 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R31 and R32 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
Preferably,
R represents a radical CR1R2,
either R, represents a hydrogen atom, and R2 represents a radical xe2x80x94C(R8) (R11) (R12) or C(R8) (R9) (R10) or R1 represents an alkyl radical and R2 represents a radical xe2x80x94C(R8) (R11) (R12)
R3 and R4 which are identical or different, represent either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94CONR22R23, hydroxyalkyl or -alkxe2x80x94NR24R25 radicals; or a heteroaromatic chosen from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, xe2x80x94CONR22R23, -alkxe2x80x94NR24R25 or hydroxyalkyl radicals,
R8 represents a hydrogen atom,
R9 represents a xe2x80x94COxe2x80x94NR26R27, xe2x80x94COOalk, xe2x80x94CH2OH, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94alk, xe2x80x94CH2xe2x80x94NHR28 or xe2x80x94NHCOOalk radical, R10 represents a radical Ar or Het, R11 represents a radical xe2x80x94SO2xe2x80x94alk, xe2x80x94SO2xe2x80x94Ar or xe2x80x94SO2xe2x80x94Het,
R12 represents represents a hydrogen atom or a radical Ar or Het,
R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monorbicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R24 and R25, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively R24 and R2, together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, xe2x80x94COOalk, xe2x80x94COxe2x80x94NHalk, xe2x80x94CSxe2x80x94NHalk, oxo or xe2x80x94COxe2x80x94NH2 radicals, Ar represents a phenyl or naphthyl radical optionally substituted with 1 or 2 subtituents chosen from a halogen atom or an alkyl, alkoxy, xe2x80x94COxe2x80x94alk, cyano, xe2x80x94COOalk, xe2x80x94CONR22R23, alkylsulfonyl, hydroxyalkyl, -alkxe2x80x94NR24R25, xe2x80x94NR24R25, hydroxyl, CF3, CF3, xe2x80x94Oxe2x80x94alkxe2x80x94NH-cycloalkyl or SO2NH2 radical,
Het represents a benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring.
The compounds of formula (I) may be provided in the form of enantiomers and diastereoisomers. These optical isomers and mixtures thereof form part of the invention.
The compounds of formula (I) for which R represents a radical CR1R2, in which R, represents a hydrogen atom and R2 represents a radical C(R8) (R11) (R12) in which R8 represents a hydrogen atom, R11 represents a radical xe2x80x94SO2xe2x80x94Ar, xe2x80x94SO2xe2x80x94Het or xe2x80x94SO2alk and R12 represents a hydrogen atom or a radical Ar or Het, and the compounds of formula (I) for which R represents a radical Cxe2x95x90C(R5)SO2R6 or Cxe2x95x90C(R7)SO2alk may be prepared according to the following reaction scheme: 
in these formulae, either Ra represents an alkyl, Het or Ar radical and Rb represents a hydrogen atom or a radical Ar or Het, or Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, or Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted with a radical -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radical, R3, R4, Ar and Het have the same meanings as in formula (I).
Reactions d and e can only be used when Rb is a hydrogen atom.
The reaction is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9215xc2x0 C.
The dehydration reaction b is generally carried out by any dehydration method known to a person skilled in the art which makes it possible to dehydrate an alcohol in order to obtain the corresponding alkene. Preferably, the acetyloxy derivative is prepared by the action of acetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between 5xc2x0 C. and 20xc2x0 C. and then the medium is treated with a base such as an alkali metal hydroxide (for example sodium hydroxide), an alkali metal carbonate (for example sodium or potassium carbonate), an amine such as a trialkylamine (for example triethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium. The acetyloxy intermediate may be isolated or otherwise. The acetyloxy may also be prepared directly in the reaction medium of reaction a.
Reduction c is generally carried out in an inert solvent such as a (1-4 C) aliphatic alcohol (for example methanol), a chlorinated solvent (for example chloroform or dichloromethane) or a mixture of these solvents, in the presence of NaBH4, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium.
Reaction d is carried out by the action of trimethylsilyl chloride, in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of n-butyllithium, at a temperature of xe2x88x9270xc2x0 C.
Reaction e is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9215xc2x0 C.
Reaction f is generally carried out in a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of 0xc2x0 C. at the boiling point of the reaction medium.
The hydrolysis g is carried out in an inert solvent such as an ether (for example dioxane), by means of hydrochloric acid, at a temperature in the region of 20xc2x0 C.
The reactions h and j are preferably carried out in an inert solvent such as acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium carbonate), at the boiling point of the reaction medium.
Reaction i is carried out under a hydrogen atmosphere, in the presence of a catalyst such as palladium or one of its derivatives, in an inert solvent such as methanol or ethanol, at a temperature of between 15xc2x0 C. and 60xc2x0 C.
Reaction k is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or chloroform) at a temperature of between 0xc2x0 C. and the boiling point of the reaction mixture.
The derivatives R3CH(Br)R4 are commercially available or may be obtained by application or adaptation of the method described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933). Generally, the corresponding alcohol R3CHOHR4 is brominated by means of hydrobromic acid, in acetic acid, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium. The corresponding alcohols R3CHOHR4 are commercially available or may be obtained by application or adaptation of the methods described by PLASZ A. C. et al., J. Chem. Soc. Chem. Comm., 527 (1972).
The intermediates of formula 2 may be obtained by application or adaptation of the methods described in the examples. In particular, the procedure is carried out according to the following reaction schemes: 
in these formulae Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, Ra and Rb have the same meanings as previously mentioned for derivative 2.
Reaction a is generally carried out in an inert solvent such as dimethylformamide or a 1-4 C aliphatic alcohol, at a temperature of between 20xc2x0 C. and 30xc2x0 C.
Reactions b and e are carried out by any known method which makes it possible to oxidize a sulfur-containing derivative without affecting the rest of the molecule such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulfuric acid), in an inert solvent such as a chlorinated solvent (for example chloroform or dichloromethane), at a temperature of between 0 and 25xc2x0 C. It is also possible to use hydrogen peroxide, optionally in the presence of a metal oxide (sodium tungstate) or a periodate (for example sodium periodate), in an inert solvent such as a 1-4 C aliphatic alcohol (for example methanol or ethanol), acetic acid, water or a mixture of these solvents, at a temperature of between 0 and 60xc2x0 C. It is also possible to carry out the procedure by means of tert-butyl hydroperoxide in the presence of titanium tetraisopropoxide in a 1-4 C aliphatic alcohol (for example methanol or ethanol) or a water-alcohol mixture, at a temperature in the region of 25xc2x0 C. or by means of oxoneR (potassium peroxymonosulfate), in a 1-4 C aliphatic alcohol (for example methanol or ethanol), in the presence of water, acetic acid or sulfuric acid, at a temperature in the region of 20xc2x0 C.
Reaction c is preferably carried out in an inert solvent such as a 1-4 C aliphatic alcohol (for example methanol or ethanol), at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Reaction d is carried out under an inert atmosphere (argon), at a temperature of between 50xc2x0 C. and the boiling point of the reaction medium.
Reaction f is generally carried out in an inert solvent such as tetrahydrofuran or an aliphatic ether (for example ethyl ether), at a temperature in the region of xe2x88x9270xc2x0 C.
Reaction g is generally carried out in an inert solvent such as dimethylformamide, an aliphatic ether (for example ethyl ether) or a 1-4 C aliphatic alcohol in the presence of a base (for example sodium hydride), at a temperature of between 0xc2x0 C. and 60xc2x0.
The derivatives of formula Rbxe2x80x94CH2-Hal are commercially available or may be obtained by application or adaptation of the methods described in the examples. In particular, the methylated derivative or the corresponding alcohol is halogenated using a halogenating agent such as hydrobromic acid, in acetic acid, at a temperature close to 20xc2x0 C. or N-bromo- or N-chlorosuccinimide in the presence of benzoyl peroxide, in an inert solvent such as tetrachloromethane, at the boiling point of the reaction medium. The methylated derivatives or the corresponding alcohols are commercially available or may be obtained according to the methods described by BRINE G. A. et al., J. Heterocyl. Chem, 26, 677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples.
The azetidinones of formula 3 may be obtained by application or adaptation of the methods described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994), or DAVE P. R., J. Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following reaction scheme: 
In these formulae, R3 and R4 have the same meanings as in formula (I) and HAL represents a chlorine or bromine atom.
In step A, the procedure is preferably carried out in an inert solvent such as a 1-4 C aliphatic alcohol (ethanol or methanol for example), optionally in the presence of an alkali metal hydroxide, at the boiling point of the reaction medium.
In step B, the reduction is generally carried out using lithium aluminum hydride, in tetrahydrofuran at the boiling point of the reaction medium.
In step C, the procedure is preferably carried out in an inert solvent such as a 1-4 C aliphatic alcohol (ethanol or methanol for example) in the presence of sodium hydrogen carbonate, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
In step D, the oxidation is preferably carried out in DMSO, using the sulfurtrioxide-pyridine complex, at a temperature close to 20xc2x0 C. or using dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between xe2x88x9270 and xe2x88x9250xc2x0 C.
In step E, the procedure is carried out according to the method described by GRISAR M. et al., in J. Med. Chem., 885 (1973). The magnesium compound of the brominated derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium. After hydrolysis with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium.
The R3xe2x80x94COxe2x80x94R4 derivatives are commercially available or may be obtained by application or adaptation of the methods described by KUNDER N. G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN N. K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE R. D. et al., J. Org. Chem., 62 (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.
The R3Br derivatives are commercially available or may be obtained by application or adaptation of the methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al., Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993).
The R4 CN derivatives are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het. Chem., 17 1333 (1980); PERCC V. et al., J. Org. Chem., 60 (21) 6895 (1995).
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 represents a hydrogen atom and R2 represents a radical C(R8) (R9) (R10) in which R8 represents a hydrogen atom, R9 represents a radical xe2x80x94COxe2x80x94NR26R27, xe2x80x94COOH, xe2x80x94COOalk, xe2x80x94CH2OH, xe2x80x94NHCOOalk or xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94alk and R10 represents a radical Ar or Het may be prepared according to the following reaction scheme: 
in these formulae R3, R4, R10, R26 and R27 have the same meanings as in formula (I) and alk represents an alkyl radical.
The derivatives of formula 4 are commercially available or may be obtained by esterification of the corresponding acids, optionally in an activated form such as the acid chloride. The acids are commercially available or may be obtained from the corresponding methylated derivatives according to the method described by J P. HANSEN et al., J. Heteocycl., 10, 711 (1973).
Reaction a is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9215xc2x0 C.
Reaction b is generally carried out by any dehydration method known to a person skilled in the art which makes it possible to dehydrate an alcohol in order to obtain the corresponding alkene and in particular the methods previously described.
The reduction c is generally carried out in an inert solvent such as an aliphatic alcohol (1-4 C) such as methanol, a chlorinated solvent such as chloroform, dichloromethane or a mixture of these solvents, in the presence of NaBH4, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium.
Reaction d is carried out by any method known to a person skilled in the art which makes it possible to pass from an ester to the corresponding acid without affecting the rest of the molecule. The procedure is preferably carried out in an inert solvent such as dioxane, in the presence of hydrochloric acid, at the boiling point of the reaction medium.
Reaction e is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule. Preferably, when the acid is used, the procedure is carried out in the presence of a condensing agent which is used in peptide chemistry such as a carbodiimide (for example N,Nxe2x80x2-dicyclohexylcarbodiimide) or N,Nxe2x80x2-carbonyldiimidazole, in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (dimethylformamide) or a chlorinated solvent (for example methylene chloride, 1,2-dichloroethane or chloroform) at a temperature of between 0xc2x0 C. and the reflux temperature of the reaction mixture. When a reactive derivative of the acid is used, it is possible to cause the anhydride, a mixed anhydride or an ester (which may be chosen from the activated or nonactivated esters of the acid) to react; the procedure is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogen-containing organic base (for example trialkylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo[4.3.0]non-5-ene), in a solvent as cited above, or a mixture of these solvents, at a temperature of between 0xc2x0 C. and the reflux temperature of the reaction mixture, or in a biphasic aqueous-organic medium in the presence of an alkaline or alkaline-earth base (sodium hydroxide or potassium hydroxide) or an alkali or alkaline-earth metal carbonate or bicarbonate at a temperature of between 0 and 40xc2x0 C.
Reaction f is carried out by CURTIUS arrangement, in the presence of diphenylphosphorazide azide and triethylamine, in toluene, at a temperature in the region of 50xc2x0 C.
For reactions g and h, the procedure is carried out directly in the reaction medium of step g at a temperature in the region of 20xc2x0 C.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94C(R8) (R9) (R10) for which R8 is a hydrogen atom, R9 is a radical xe2x80x94CH2xe2x80x94NHR28 and R10 represents a radical Ar or Het, may be prepared according to the following reaction scheme: 
In these formulae, R3, R4 and R10 have the same meanings as in formula (I), Rd represents an alkyl or phenyl radical, Re represents an alkyl radical, Rf represents an alkyl radical, R9 represents an alkyl, cycloalkylalkyl, cycloalkyl, xe2x80x94(CH2)nOH radical, n is equal to 1, 2 or 3.
Step a is generally carried out in an inert solvent such as an aliphatic alcohol (1-4C) (for example methanol), in a chlorinated solvent (for example dichloromethane or dichloroethane) or tetrahydrofuran, in the presence of a base such as NaBH(OCOCH3)3, at a temperature in the region of 20xc2x0 C.
Step b is generally carried out in an inert solvent such as a halogenated solvent (for example dichloromethane), in the presence of an organic base such as triethylamine or dimethylaminopyridine, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium.
Step c is generally carried out in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (for example chloroform or 1,2-dichloroethane), an aromatic solvent (for example benzene or toluene), at a temperature of between 10xc2x0 C. and the boiling point of the reaction medium.
Step d is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
The derivatives 6 may be obtained according to the following reaction scheme: 
In these formulae, R3, R4 and R10 have the same meanings as in formula (I) and Ms is a methylsulfonyloxy radical.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of triethylamine, at a temperature of between 10 and 20xc2x0 C.
Step b is generally carried out with liquid aqueous ammonia in methanol, in an autoclave, at a temperature in the region of 60xc2x0 C.
The compounds of formula (I) in which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 is a radical xe2x80x94CONR13R14 may be prepared according to the following reaction scheme: 
In these formulae, R3, R4, R13 and R14 have the same meanings as in formula (I), Ms represents a methylsulfonyloxy radical and Et represents ethyl.
Step a is carried out in the presence of triethylamine, in an inert solvent such as an ether (for example tetrahydrofuran), at a temperature in the region of 0xc2x0 C.
Step b is generally carried out in an inert solvent such as a mixture of water and dimethylformamide, at a temperature of between 30 and 75xc2x0 C.
Step c is carried out by any method known to a person skilled in the art which makes it possible to pass from a cyanated compound to the corresponding acid without affecting the rest of the molecule. Preferably, the procedure is carried out by means of potassium hydroxide in an aliphatic alcohol (1-4C) (for example ethanol) or in an aqueous medium, at the boiling point of the reaction medium.
Step d is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred methods previously described.
The compounds of formula (I) for which R represents a radical CR1R2 in which R, is a hydrogen atom and R2 is a radical xe2x80x94CH2xe2x80x94CONR13R14 may be prepared according to the following reaction scheme: 
In these formulae, R3, R4, R13 and R14 have the same meanings as in formula (I) and Et represents an ethyl radical.
Reaction a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as sodium hydride, or an alkali metal carbonate (for example potassium carbonate), at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Reaction b is generally carried out by means of NaBH4, in ethanol, at a temperature in the region of 0xc2x0 C.
Reaction c is carried out by any method known to a person skilled in the art which makes it possible to pass from an ester to the corresponding acid without affecting the rest of the molecule. The procedure is preferably carried out in an inert solvent such as dioxane, in the presence of hydrochloric acid, at the boiling point of the reaction medium.
Reaction d is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred methods previously described.
The intermediates 7 may also be obtained by malonic synthesis according to the following reaction scheme: 
In these formulae, Ms represents a methylsulfonyloxy radical, R3 and R4 have the same meanings as in formula (I).
Reaction a is generally carried out by the action of diethyl malonate, in an inert solvent such as tetrahydrofuran, in the presence of freshly prepared sodium ethoxide, at the boiling point of the reaction medium.
Reaction b is generally carried out in an aqueous solution of hydrochloric acid at the boiling point of the reaction medium.
The compounds In may also be obtained according to the following reaction scheme: 
In these formulae, R3, R4, R13 and R14 have the same meanings as in formula (I).
Step a is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred methods previously described.
Step b is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as sodium hydride or potassium carbonate, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
The reduction of step c is generally carried out by means of NaBH4, in ethanol, at a temperature in the region of 20xc2x0 C.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94SOR6 or xe2x80x94SO2R6 may be prepared according to the following reaction scheme: 
In these formulae, R3, R4 and R6 have the same meanings as in formula (I) and Ms is a methylsulfonyloxy radical.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of an inorganic base such as sodium hydride, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium.
Step b is generally carried out by any method of persons skilled in the art for oxidizing a sulfur-containing derivative, such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulfuric acid), in an inert solvent such as a chlorinated solvent (for example chloroform or dichloromethane), at a temperature of between 0 and 25xc2x0 C. or alternatively by means of oxone in a water-alcohol (methanol or ethanol) mixture.
Step c is generally carried out by any method of persons skilled in the art for oxidizing a sulfinyl derivative. Preferably, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or alternatively by means of oxone, in a water-alcohol (methanol or ethanol) mixture.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94COR6 or xe2x80x94COxe2x80x94cycloalkyl may be prepared according to the following reaction scheme: 
In these formulae, R3 and R4 have the same meanings as in formula (I) and Rh has the same meanings as R6 or represents a cycloalkyl radical (3 to 10 carbon atoms).
Step a is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
Step b is generally carried out in an inert solvent such as an ether such as tetrahydrofuran, at a temperature in the region of 0xc2x0 C. The organomagnesium compounds are prepared according to methods known to a person skilled in the art, such as those described in the examples.
The compounds of formula (I) for which R1 is a hydrogen atom and R2 is a radical xe2x80x94C(OH) (R6) (R12), xe2x80x94C(OH) (R6) (alkyl), xe2x80x94C(xe2x95x90NOxe2x80x94CH2xe2x80x94CHxe2x95x90CH2)R6 or xe2x80x94C(xe2x95x90NOalk)R6 may be prepared according to the following reaction scheme: 
In these formulae, R3, R4 and R6 have the same meanings as in formula (I), Ri has the same meanings as R12 or represents an alkyl radical (1 to 6 carbon atoms in a straight or branched chain) and Rj represents an alkyl radical (1 to 6 carbon atoms in a straight or branched chain) or xe2x80x94CH2xe2x80x94CHxe2x95x90CH2.
Step a is generally carried out in an inert solvent such as an aliphatic alcohol (for example ethanol), in the presence of sodium acetate, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Step b is generally carried out in an inert solvent such as an ether such as tetrahydrofuran, at a temperature in the region of 0xc2x0 C. The organomagnesium compounds are prepared according to methods known to a person skilled in the art, such as those described in the examples.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, in which R31 and R32 are hydrogen atoms or radicals xe2x80x94CH(R6)NHSO2alk, xe2x80x94CH(R6)NHCONHalk or xe2x80x94CH(R6)NHCOR31, may be prepared according to the following reaction scheme: 
In these formulae, R3, R4, R6 and R31 have the same meanings as in formula (I), Ms represents a methylsulfonyloxy radical and alk represents an alkyl radical.
Reaction a is generally carried out by means of NaBH4 in ethanol, at a temperature in the region of 20xc2x0 C.
Step b is carried out in the presence of triethylamine, in an inert solvent such as an ether (for example tetrahydrofuran), at a temperature in the region of 0xc2x0 C.
Step c is carried out by means of liquid aqueous ammonia in methanol, in an autoclave at a temperature in the region of 60xc2x0.
Step d is generally carried out in an inert solvent such as a halogenated solvent (for example dichloromethane) or tetrahydrofuran, in the presence of an organic base such as triethylamine, dimethylaminopyridine, at a temperature in the region of 20xc2x0 C.
Step e is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
Step f is generally carried out by means of an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (for example chloroform or dichloroethane), an aromatic solvent (for example benzene or toluene), at a temperture of between 10xc2x0 C. and the boiling point of the reaction medium.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical may be prepared by the action of a halide HalR31 on a compound of formula (I) for which R represents a radical CRIR2 in which R, is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 and R32 are hydrogen atoms.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0xc2x0 C. and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 is a hydrogen atom and R32 is an alkyl radical may also be prepared by the action of a corresponding compound of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94COxe2x80x94R6 on an amine HNR31R32 for which R31 is a hydrogen atom and R32 is an alkyl radical.
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or dichloroethane), in the presence of a reducing agent such as sodium triacetoxy-borohydride, at a temperature of between 0xc2x0 C. and 70xc2x0 C.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 and R32 are alkyl, Ar or -alkxe2x80x94Ar radicals may be prepared by the action of a halide HalR32 on a compound of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alkxe2x80x94Ar radical.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0xc2x0 C. and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 is a hydrogen atom and R32 is a (2-6C) alkyl or -(2-6C)alkxe2x80x94Ar radical may be prepared by the action of an aldehyde RaCHO for which Ra is an alkyl or -alk-Ar radical on a compound of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 and R32 are hydrogen atoms.
This reaction is carried out in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran, at a temperature of between 0xc2x0 C. and 50xc2x0 C. in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
The compounds of formula (I) for which R represents a radical CR1R2 in which R, is a hydrogen atom and R2 represents a radical xe2x80x94CH(RG)NR31R32, R31 is an alkyl, Ar or -alk-Ar radical and R32 is a (2-6C) alkyl or -(2-6C)alk-Ar radical may be prepared by the action of an aldehyde RaCHO for which Ra is an alkyl or -alkxe2x80x94Ar radical on a compound of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alkxe2x80x94Ar radical.
This reaction is carried out in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran, at a temperature of between 0xc2x0 C. and 50xc2x0 C. in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 and R32 form with the nitrogen atom to which they are attached a heterocycle chosen from aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl may be prepared by the action of a dihalide Hal-(2-5C)alk-Hal on a compound of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH(R6)NR31R32, R31 and R32 are hydrogen atoms.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0xc2x0 C. and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 is a hydrogen atom and R2 represents a radical xe2x80x94CH2xe2x80x94COR6, xe2x80x94CH2xe2x80x94CH(R6)xe2x80x94NR31R32 or xe2x80x94CH2xe2x80x94C(xe2x95x90NOalk)R6 may be prepared according to the following reaction scheme: 
In these formulae, R3, R4, R6, R31 and R32 have the same meanings as in formula (I) and alk represents an alkyl radical.
Step a is generally carried out in a solvent such as tetrahydrofuran, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Step b is generally carried out in an inert solvent such as an aliphatic alcohol (for example methanol), a chlorinated solvent (chloroform or dichloromethane) or a mixture of these solvents, in the presence of a reducing agent such as NaBH4, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium.
Step c is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
Step d is generally carried out in an inert solvent such as an ether such as tetrahydrofuran, at a temperature in the region of 0xc2x0 C. The organomagnesium compounds are prepared according to the mxe2x80x2yhodes known to a person skilled in the art such as those described in the examples.
Step e is generally carried out in an inert solvent such as a 1-4C aliphatic alcohol such as methanol, in the presence of sodium acetate, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Step f is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or dichloroethane), in the presence of a reducing agent such as sodium triacetoxyborohydride, at a temperature of between 0xc2x0 C. and 70xc2x0 C.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 represents a cyano, xe2x80x94Sxe2x80x94alkxe2x80x94NR16R17, xe2x80x94NHR15, alkyl or xe2x80x94NR20R21 radical and R2 represents a radical xe2x80x94C(R8) (R11) (R12) in which R8 is a hydrogen atom may be prepared according to the following reaction scheme: 
In these formulae, R3, R4, R11, R12, R15, R16 and R17 have the same meanings as in formula (I), alk represents an alkyl radical, Hal represents a halogen atom and M represents a metal and preferably copper.
Step a is preferably carried out in a polar solvent such as dimethyl sulfoxide, at a temperature of between 20 and 50xc2x0 C.
Step b is preferably carried out in an inert solvent such as dimethyl sulfoxide, tetrahydrofuran or acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Step c is preferably carried out in an inert solvent such as dimethyl sulfoxide, tetrahydrofuran or acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
Step d is preferably carried out in an inert solvent such as an ether (ethyl ether) or tetrahydrofuran, at a temperature of between xe2x88x9278xc2x0 C. and 20xc2x0 C.
Step e is preferably carried out in an inert solvent such as dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20xc2x0 C. and the boiling point of the reaction medium.
The compounds of formula (I) for which R represents a radical CR1R2 in which RI represents a radical -alkxe2x80x94NR18R19, R18 and R19 represent a hydrogen atom may be prepared by reducing the corresponding compound of formula (I) for which R represents a radical CR1R2 in which R1 represents a cyano radical.
This reaction is generally carried out in an inert solvent such as tetrahydrofuran, ethyl ether or toluene, at a temperature of between 0xc2x0 C. and the boiling point of the reaction medium, in the presence of a reducing agent such as aluminum hydride.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 represents a radical -alkxe2x80x94NR18R19, R18 represents a hydrogen atom and R19 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, xe2x80x94SO2alk, xe2x80x94COxe2x80x94NHalk or xe2x80x94COOalk radical may be prepared by the action of a halide HalR19, Hal represents a halogen, on a compound of formula (I) for which R represents a radical CR1R2 in which R1 represents a radical -alkxe2x80x94NR18BR9, R18 and R19 represent a hydrogen atom.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0xc2x0 C. and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CR1R2 in which R1 represents a radical -alkxe2x80x94NR18R19, R18 represents an alkyl radical and R19 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, xe2x80x94SO2alk, xe2x80x94COxe2x80x94NHalk or xe2x80x94COOalk radical may be prepared by the action of an alkyl halide on a compound of formula (I) for which R represents a radical CR1R2 in which R1 represents a radical -alkxe2x80x94NR18R19, R18 represents a hydrogen atom and R19 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, xe2x80x94SO2alk, xe2x80x94COxe2x80x94NHalk or xe2x80x94COOalk radical.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0xc2x0 C. and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CR1R2 in which either R1 represents a hydrogen atom and R2 represents a radical xe2x80x94C(R8) (R9) (R10) or xe2x80x94C(R8) (R11) (R12), or R1 represents an alkyl, NHxe2x80x94R15, cyano, xe2x80x94Sxe2x80x94alkxe2x80x94NR16R17, -alkxe2x80x94NR18R19 or xe2x80x94NR20R21 radical and R2 represents a radical xe2x80x94C(R8) (R11) (R12) and R8 represents an alkyl radical may be prepared by alkylation of a corresponding compound of formula (I) for which R8 is a hydrogen atom.
This reaction is preferably carried out by means of a base such as an alkali metal hydride (for example sodium hydride), an alkali metal amide (for example sodium amide) or an organometallic derivative, in an inert solvent such as an aliphatic ether (ethyl ether) or tetrahydrofuran, at a temperature of between xe2x88x9278xc2x0 C. and 30xc2x0 C., by means of an alkylating agent such as an alkyl halide or an alkyl sulfonate.
The compounds of formula (I) for which R represents a radical Cxe2x95x90C(R7)SO2alk may also be prepared according to the following reaction scheme: 
In these formulae, R3, R4 and R7 have the same meanings as in formula (I), alk represents an alkyl radical and Hal represents a halogen atom.
Reaction A is generally carried out in an inert solvent such as an ether (for example ethyl ether), in the presence of a strong base such as tert-butyllithium or n-butyllithium, at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9250xc2x0 C., followed by the addition of sulfur and then an alkyl halide (for example iodide or bromide).
Reaction B is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium or n-butyllithium, at a temperature of between xe2x88x9270xc2x0 C. and xe2x88x9250xc2x0 C., followed by the addition of azeditin-3-one, a return to room temperature and hydrolysis.
Reaction C is carried out by any known method which makes it possible to oxidize a sulfur-containing derivative without affecting the rest of the molecule, such as those previously described.
It is understood for persons skilled in the art that, to carry out the processes according to the invention which are described above, it may be necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to avoid side reactions. These groups are those which allow removal without affecting the rest of the molecule. As examples of groups protecting the amino function, there may be mentioned tert-butyl or methyl carbamates which may be regenerated using iodotrimethylsilane or allyl using palladium catalysts. As examples of groups protecting the hydroxyl function, there may be mentioned triethylsilyl and tert-butyldimethylsilyl which may be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals (methoxymethyl or tetrahydropyranyl for example) with regeneration using hydrochloric acid. As groups protecting carboxyl functions, there may be mentioned esters (allyl or benzyl for example), oxazoles and 2-alkyl-1,3-oxazolines. Other protecting groups which can be used are described by GREENE T. W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley and Sons.
The compounds of formula (I) may be purified by the customary known methods, for example by crystallization, chromatography or extraction.
The enantiomers of the compounds of formula (I) may be obtained by resolution of the racemates for example by chromatography on a chiral column according to PIRCKLE W. H. et al., Asymmetric synthesis, Vol. 1, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers may be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors).
The compounds of formula (I) may be optionally converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention.
As examples of pharmaceutically acceptable salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methane sulfonate, methylene-bis-xcex2-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate.
The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds possess a high affinity for the cannabinoid receptors and particularly those of the CB1 type. They are CB1 receptor antagonists and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal apparatus and reproductive disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992).
Accordingly, these compounds may be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine, Parkinson""s disease, Alzheimer""s disease, Huntington""s chorea, Raynaud""s syndrome, tremor, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette""s syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, in weaning from chronic treatments and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators of the analgesic activity of the narcotic and nonnarcotic drugs. They may also be used for the treatment or prevention of intestinal transit.
The affinity of the compounds of formula (I) for the cannabis receptors has been determined according to the method described by KUSTER J. E., STEVENSON J. I., WARD S. J., DIAMBRA T. E., HAYCOCK D. A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).
In this test, the IC50 of the compounds of formula (I) is less than or equal to 1000 nM.
Their antagonist activity has been shown by means of the model of hypothermia induced by an agonist of the cannabis receptors (CP-55940) in mice, according to the method described by Pertwee R. G. in Marijuana, Harvey D. J. eds, 84 Oxford IRL Press, 263-277 (1985).
In this test, the DE50 of the compounds of formula (I) is less than or equal to 50 mg/kg.
The compounds of formula (I) exhibit low toxicity. Their LD50 is greater than 40 mg/kg by the subcutaneous route in mice.
The preferred compounds of formula (I) are the following:
(RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine,
(R)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine,
(S) 7-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine,
(RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)-(methylsulfonyl)methyl]azetidine,
(R)-1-[bis (4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)-(methylsulfonyl)methyl]azetidine,
(S)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)-(methylsulfonyl)methyl]azetidine,
(RS)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl]azetidine,
(R)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(S)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-1-yl-phenyl]methylsulfonylmethyl}azetidine,
1-[bis(4-chlorophenyl)methyl]-3-(R)-{[3-azetidin-1-yl-phenyl]methylsulfonylmethyl}azetidine,
1-[bis(4-chlorophenyl)methyl]-3-(S)-{[3-azetidin-1-yl-phenyl]methylsulfonylmethyl}azetidine,
(RS)-1-[3({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methyl sulfonylmethyl) phenyl]pyrrolidine,
(R)-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methyl sul fonylmethyl) phenyl]pyrrol idine,
(S)-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]pyrrolidine,
(RS)xe2x80x94Nxe2x80x94[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylamine,
(R)xe2x80x94Nxe2x80x94[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]-N-methylamine,
(S)xe2x80x94Nxe2x80x94[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]-N-methylamine,
(RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistrifluoromethylphenyl)methylsulfonylmethyl]azetidine,
(R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistrifluoromethylphenyl)methylsulfonylmethyl]azetidine,
(S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistrifluoromethylphenyl)methylsulfonylmethyl]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-(phenylsulfonylmethyl)-azetidine,
(RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-3-methylazetidine,
(R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-3-methylazetidine,
(S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-3-methyl-azetidine,
(RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide,
(R)-2-{1-[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide,
(S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide,
(RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide,
(R)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide,
(S)-2-{1-[bis(4-chlorophenyl)methyl]azetidiri-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide,
(RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide,
(R)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide,
(S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide,
(RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide,
(R)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide,
(S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide,
(RS)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonylethyl]azetidine,
(R)-1-[bis (4-chlorophenyl)methyl]-3-[1-(3, 5-difluorophenyl)-1-methylsulfonylethyl]azetidine,
(S)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonylethyl]azetidine,
(RS)-1-[bis (4-fluorophenyl) methyl]-3-[(3,I5-difluorophenyl)methyl sulfonylmethyl]azetidine, (R)-1-[bis (4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(S)-1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(RS)-p1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(SS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(RR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(SR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)mrethylsulfonylmethyl]azetidine,
(SS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl]azetidine,
(RR)-{1-[(4-pyridyl)-(4-chlorophenyl)mnethyl]-3-[(3,5-difluarophenyl) methylsulfonylmethyl]azetidine,
(SR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-2dethylsulfonylmethyl]azetidin-1-yl}methyl)pyrimidine,
(SR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1-yl}methyl)pyrimidine,
(RR)-5-((4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1-yl}methyl)pyrimidine,
(SS)-5-((4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1-yl}methyl)pyrimidine,
(SS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine,
(RR)-{l-(2-chloropyrid-5-yl)-(4-chlorophenyl)mnethyl]-3-[(3, 5-difluorophenyl)methylsulfonylmethyl]azetidine,
(RS) {11 [(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl]azetidine,
(SR)-1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, their optical isomers and their pharmaceutically acceptable salts.
The following examples illustrate the invention.